What we already know about this topic

Even though it is one of the most difficult clinical situations to manage in the Emergency Department, good evidence for optimal treatment of acute agitation due to psychosis is still lacking. As a consequence, documents from Scientific Societies disagree about which drug employ to quickly sedate the agitated patient, as synthetized in table 1.

Scientific society

Recommendations for pharmacological tranquillisation

AAEP 2012 (1)

First choice: i.m. ziprasidone or i.m. olanzapine Second line: benzodiazepine such as lorazepam.

NICE 2015 (2)

i.m. lorazepam, i.m. haloperidol + i.m. promethazine Prefer i.m. lorazepam if there is insufficient information to guide the choice or the patient has not taken antipsychotic medication before.

NSWH 2015 (3)

First choice: droperidol, Second choice: Benzodiazepines, ketamine.

ACEP 2017 (4)

Ketamine is one option for immediate sedation of the severely agitated patient who may be violent or aggressive. (Consensus recommendation)

Table 1. These documents refer primarily to “acute agitation” or “acute behavioral disturbances” in the Emergency Department, and only a part of them addresses specifically psychosis-induced acute agitation. Abbreviations: AAEP, American Association for Emergency Psychiatry; NICE, National Institute for Health and Care Excellence; NSWH, New South Wales Ministry of Health; ACEP, American College of Emergency Physicians, im: intramuscolar

For this reason, more evidence is needed to clarify which pharmacological agent is to prefer in such a clinical situation. Haloperidol is a typical, first generation, anti-psychotic and today still represents one of most employed drugs to treat acute manifestations of psychosis. Which is its efficacy in controlling acute psychosis-induced agitation? The work from the Cochrane Collaboration we look at try to answer this question, summarizing the evidence from the published randomized controlled trials confronting haloperidol with placebo or other active pharmacological agents.

Quality of included studies:the vast majority of the studies have high or unclear risk of bias for more than half of the methodological aspects evaluated.

Number of patients: 4933

Results:

Haloperidol vs. placebo

Outcome

No. of studies / No. of patients

Risk Ratio

(95% C.I.)

Quality of evidence

Not asleep at 2 hours

2 / 220

0,88 (0,82 – 0,95)

Very low

Needing additional injection within 24 hours

4 / 660

0,51 (0,42 – 0,62)

Low

One or more drug related adverse events over 24 hours

2 / 395

1,64 (1,22 – 2,20)

Dystonia during 24 hours

2 / 207

7,49 (0.93 – 60,21)

Risk ratio below 1 favors haloperidol

Haloperidol vs. chlorpromazine

Outcome

No. of studies / No. of patients

Risk Ratio

(95% C.I.)

Quality of evidence

Not asleep at 2 hours

1 / 39

1,93 (1,04 – 3,60)

Very low

Needing additional injection within 24 hours

1 /30

1,07 (0,89 - 1,28)

Very low

One or more drug related adverse events over 24 hours

Not available

Extra-piramidal adverse effects

2 / 69

2,07 (0,28 – 15,15)

Risk ratio below 1 favors haloperidol

Haloperidol vs. haloperidol + promethazine

Outcome

No. of studies / No. of patients

Risk Ratio

(95% C.I.)

Quality of evidence

Not asleep at 20 minutes

1 / 316

1,60 (1,18 – 2,16)

Moderate

Needing additional injection within 24 hours

2 / 376

0,78 (0,43 – 1,41)

Very low

One or more drug related adverse events over 24 hours

2 / 376

2,01 (1,07- 3,80)

Acute dystonia

1 / 361

19,48 (1,14 – 331,92)

Low

Risk ratio below 1 favors haloperidol

Haloperidol vs. lorazepam

Outcome

No. of studies / No. of patients

Risk Ratio

(95% C.I.)

Quality of evidence

Not asleep at 3 hours

1 / 60

1,05 (0,76 – 1,44)

Very low

Needing additional injection within 24 hours

1 / 66

1,14 (0,91 – 1,43)

Very low

One or more drug related adverse events over 24 hours

Not available

Dystonia during 24 hours

1 / 66

3,54 (0,42 – 30,03)

Very low

Risk ratio below 1 favors haloperidol

Haloperidol vs. midazolam

Outcome

No. of studies / No. of patients

Risk Ratio

(95% C.I.)

Quality of evidence

Not asleep at 3 hours

Not available

Needing rescue drug

1 / 84

1,14 (0,46 – 2,87)

One or more drug related adverse events over 24 hours

1 / 84

5,0 (0,25 – 101,11)

Low

Apnoea

1 / 84

3,0 (0,13 – 71,61)

Risk ratio below 1 favors haloperidol

Haloperidol vs. haloperidol + lorazepam

Outcome

No. of studies / No. of patients

Risk Ratio

(95% C.I.)

Quality of evidence

Not asleep at 3 hours

1 / 67

1,83 (1,11 – 3,02)

Very low

Needing additional injection within 24 hours

1 / 67

1,05 (0,87 – 1,27)

Very low

One or more drug related adverse events over 24 hours

1 / 67

1,16 (0,62 – 2,18)

Very low

Dystonia during 24 hours

1 / 67

8,25 (0,46–147,45)

Risk ratio below 1 favors haloperidol

Haloperidol vs. haloperidol + midazolam

Outcome

No. of studies / No. of patients

Risk Ratio

(95% C.I.)

Quality of evidence

Not asleep at 2 hours

Not available

Needing additional injection within 24 hours

1 / 60

0,88 (0,69 – 1,13)

Very low

One or more drug related adverse events over 24 hours

Not available

Dystonia during 24 hours

Not available

Risk ratio below 1 favors haloperidol

Comment and conclusions

The modest relevance of the results of the present systematic review reflects the scarcity of data regarding the treatment of acute agitation in patients with psychosis. Indeed, most of the proposed comparisons are based on just one study, frequently with a small sample. Moreover, quality of the included studies is low (above all because of a high prevalence of bias in blinding procedures and of a substantial risk of selective reporting). For these reasons quality of evidence has been correctly labeled as low or very low.

Apart from some general recommendations shared by most of the available guidelines, namely to use drugs only if nonpharmacological strategies of tranquillisation failed (1,3), and to avoid complete sedation favoring simply the reaching of a drowsiness (1,3), much uncertainty is still present in this clinical field. Haloperidol appeared more effective than placebo at the cost of increased risk of adverse effects, mainly extrapyramidal ones. No firm conclusions can be drawn regarding the efficacy and safety of haloperidol with respect to benzodiazepines, alone or as an association.

New South Wales Ministry of Health. Management of patients with Acute Severe Behavioural Disturbance in Emergency Departments. Document n.°: Published: 10 August 2015.

American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on the Adult Psychiatric Patient. Clinical Policy: Critical Issues in the Diagnosis and Management of the Adult Psychiatric Patient in the Emergency Department. Ann Emerg Med. 2017;69:480-498.

Notes: doses and modes of administration of cited drugs

Drug

Dose as indicated by Italian regulatory Agency (AIFA)

Range of doses employed in cited studies

Haloperidol

5 mg i.m.; repeat dose every hour until symptom relief or a total dose of 20 mg has been reached over 24 hours.I.v. administration is not allowed

1 to 7,5 mg (mainly 5 mg)

Counterindications as indicated by the Italian Regulatory Agency (AIFA)

· Hypersensitivity to the drug

· Coma, or CNS depression due to alcohol or other psychotropic substances. · Parkinson’s disease